1. Field of the Invention
The present invention relates to a process for purifying Iopamidol and, more particularly, to a process for purifying Iopamidol using butanol as solvent.
2. Discussion of the Background
Iopamidol is the International non-proprietary Name (INN) for L-5-xcex1-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide). This compound was first described by the Swiss company Savac A. G. in the British patent no. 1,472,050. Iopamidol is used in diagnostics as non-ionic contrast medium.
Iopamidol is a white high-melting solid. Conventional syntheses of Iopamidol involve a final purification of the product in an aqueous solution. Thereafter, in order to obtain the product in solid form, it is necessary to crystallize it.
British patent No. 1,472,050 describes that Iopamidol can be isolated by evaporation of the aqueous solution followed by crystallization of the crude product obtained from ethanol. WO 88/09328 to Bracco Industria Chimica S.p.A. describes that crude Iopamidol can be obtained by evaporation of the aqueous solution followed by crystallization of the crude product from absolute ethanol. xe2x80x9cAnalytical Profiles of Drug Substancesxe2x80x9d, vol. 17, pages 115-154, Academic Press, San Diego, 1988) describes that Iopamidol can be crystallized from water, with very slow kinetics, yielding a monohydrate or pentahydrate crystalline product.
Unfortunately when Iopamidol is crystallized from water or ethanol as described in the literature, a crystalline form having the required pharmaceutical properties as described in US Pharmacopoeia XXII, page 712, cannot be obtained. The product crystallized from ethanol contains an amount of ethanol corresponding to 4000-8000 ppm which cannot be removed either by heating at high temperatures or under vacuum. This product is not suitable as a pharmaceutical because its ethanol content is too high (the USA Pharmacopoeia requires that no impurity can exceed 5000 ppm). Similarly, Iopamidol crystallized from water is not suitable because in order to remove the water of crystallization, very long heating times at temperatures higher than 100xc2x0 C. are required. Furthermore, the yield of the crystallization from water is very poor and therefore the process is not suitable from an industrial point of view.
The literature data regarding the solubility of Iopamidol conflict with each other and therefore they do not suggest other practical solutions to solve these problems. For example, British patent no. 1,472,050 reports that Iopamidol dissolves very easily in water, has a practically unlimited solubility in methanol and has solubility in ethanol of about 10% at room temperature. However, one of the inventors of that patent, in a subsequent paper published on Boll. Chim. Farm., 120, 639, (1981), reports that Iopamidol is very soluble in water but is only slightly soluble in methanol and practically insoluble in ethanol, diethylether, benzene and chloroform. Accordingly, it is desirable to find a practical and efficient method for purifying Iopamidol.
Accordingly, it is one object of the present invention to provide a method for purifying Iopamidol from a crude solid form of Iopamidol.
It is a second object of the present invention to provide a process for purifying Iopamidol from an aqueous solution of Iopamidol.
It is a third object of the present invention to provide essentially pure Iopamidol.
The present inventors have now surprisingly found that these and other objects can be achieved by crystallizing Iopamidol from n-butanol, sec-butanol, isobutanol or t-butanol. The present inventors have further found that it is not necessary to start from solid crude Iopamidol but it is possible to obtain the desired product by directly treating an aqueous solution of Iopamidol with n-butanol, sec-butanol, isobutanol or t-butanol.
The terms n-butanol, sec-butanol, isobutanol and t-butanol are the common names used to indicate the four isomers of butanol having the formula C4H10O; more precisely, n-butanol is the common name for 1-hydroxybutane, sec-butanol is the common name for 2-hydroxybutane, isobutanol is the common name for 1-hydroxy-2-methylpropane and t.butanol is the common name for 1,1-dimethyl-1-hydroxyethane. Hereinafter, for the sake of simplicity, the term butanol is used to indicate indifferently n-butanol, sec-butanol, isobutanol or t-butanol, if not otherwise specified.
Iopamidol can be synthesized using known techniques such as those described in U.S. Pat. No. 4,001,323; incorporated herein by reference. Crude Iopamidol can be isolated as described in British patent no. 1,427,050; WO 88/09328 and xe2x80x9cAnalytical Profiles of Drug Substances, vol. 17, pages 115-154, Academic Press, San Diego; each of which is incorporated herein by reference. Preferably, Iopamidol is isolated by distillation until crude Iopamidol begins to crystallize.
Thereafter pharmaceutically pure Iopamidol is isolated by crystallizing crude Iopamidol from butanol. In a first embodiment solid crude Iopamidol is crystallized from butanol. In a second embodiment, an aqueous solution of crude Iopamidol is crystallized by adding butanol to form a crystallization mixture. The amount of residual water in the crystallization mixture, for example even an amount of water equal to the weight of Iopamidol, does not effect either the quality or the yield of pure Iopamidol.
The amount of butanol to be used is from 3 to 20 times (volume/weight) with respect to the amount of Iopamidol which is present in the aqueous solution. Preferably, the amount of butanol is from 3 to 12 times (volume/weight) with respect to the amount of Iopamidol. Still more preferably, the amount of butanol is from 3 to 10 times (volume/weight) with respect to the amount of Iopamidol. It is self-evident that when there is an azeotropic mixture, butanol can be recovered by distillization and recycled.
In a third embodiment of the present invention, a third solvent can also be added to the crystallization mixture of water, Iopamidol and butanol. The third solvent suitably is able to form a ternary azeotrope with water. A preferred third solvent is toluene.
From a practical point of view, the direct use of an aqueous solution of Iopamidol is preferred because it is practically and economically more advantageous not to remove all the water and because the resultant product has a very low content of residual solvent. It is particularly advantageous from an industrial point of view to purify Iopamidol from an aqueous solution of Iopamidol and butanol in an amount from 3 to 20 times (volume/weight) with respect to that of Iopamidol. The reaction mixture is heated at the boiling temperature to azeotropically remove part of the water. Precipitation of Iopamidol is observed. The distillation is continued until the water is reduced to an weight amount equal to or lower than that of Iopamidol. Then, the heating is stopped and the temperature is brought to 10-30xc2x0 C., preferably to about 25xc2x0 C., and Iopamidol is separated by filtration.
Alternatively, the crystallization mixture of water, Iopamidol and butanol is added with a third solvent able to from an azeotrope with water, for example toluene. As above, during the distillation step a precipitate of Iopamidol begins to form.
Iopamidol obtained by the process of the present invention is pharmaceutically acceptable since the amount of butanol remaining in the product is decidedly lower than the required limits. As used herein, pure Iopamidol contains an amount of residual solvent which is less than the amount of residual solvent in the crude Iopamidol used as the starting material. Preferably, the pure Iopamidol obtained has at most 2000 ppm of residual solvent. In fact, when Iopamidol is obtained directly from the aqueous solution, the residual solvent is even equal to or lower than 200 ppm. The resultant product has a very high chromatographic purity, higher than hat of the starting product in aqueous phase. Thus, the Iopamidol obtained by the purification process of the invention is particularly suitable for the preparation of non-ionic contrast media according to usual techniques.
Furthermore, the crystallization yields are very high, at least higher than 80% and in most cases also higher than 95%.
As far as the instant process is concerned, mixtures of butanols appear to behave in substantially the same way as the single components and thus mixture of butanols do not depart from the spirit of this invention.